COVIDMED – An early pandemic randomized clinical trial of losartan treatment for hospitalized COVID-19 patients

Objectives To assess the efficacy and safety of losartan for COVID-19 patients. Methods COVIDMED was a double-blinded, placebo-controlled platform RCT. Enrollees were randomized to standard care plus hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued early. We report losartan data vs. combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint was the mean COVID-19 Ordinal Severity Score (COSS) slope of change. Slow enrollment prompted early termination. Results Fourteen patients were included in our final analysis (losartan [N = 9] vs. control [N = 5] [lopinavir/ritonavir [N = 2], placebo [N = 3]]). Most baseline parameters were balanced. Losartan treatment was not associated with a difference in mean COSS slope of change vs. combined (p = 0.4) or placebo-only control (p = 0.05) (trend favoring placebo). 60-day mortality and overall AE/SAE rates were insignificantly higher with losartan. Conclusion In this small RCT in hospitalized COVID-19 patients, losartan did not improve outcome and was associated with adverse safety signals.

Post-consent, patients were allocated in a 2:2:2:1 ratio in blocks to one of the above four treatment groups using a statistician/computergenerated randomization schedule (without stratification). Allocation concealment was ensured by having only the enrollment research nurse be unblinded and maintaining allocation confidentiality. All groups received standard care and were followed for 60 days.
Key inclusion criteria were: hospitalized; ≥18 years-old; laboratoryconfirmed SARS-CoV-2; and randomization within 72 h. Key losartan group exclusion criteria included: taking ACEi/ARB; hypotension; hyperkalemia; renal dysfunction/volume depletion. There were no placebo group exclusions. After hydroxychloroquine/lopinavir-ritonavir enrollment ceased, inclusion/exclusion criteria were the same for losartan and placebo. Study drug (losartan or TicTacs placebo [lopinavir-ritonavir in 2 patients]) was inserted into blank capsules by a pharmacist. Dosing was initially twice daily to mask varying regimens. Losartan and lopinavir/ ritonavir doses were 25 mg and 400/100 mg, respectively. After hydroxychloroquine/lopinavir/ritonavir enrollment ceased, losartan and placebo dosing were daily for 5-14 days.
An arbitrary sample size of 4000 was chosen at the pandemic onset, with interim analysis optimization upon enrollment of 114 treatment and 57 placebos groups subjects, however, the study was terminated beforehand.
AEs were classified in accordance with NCICTC for Adverse Events, version 4.0. COVIDMED was carried out in accordance with principles of protection of humans participating in research, including the Declaration of Helsinki, and consent from all participants.

Statistical analysis
Mean slopes of change in COSS over time served as the primary endpoint for each subject. Continuous and categorical secondary endpoints were compared using Student's t-test and Fisher's exact test. Small N prompted omitting adjusted and subgroup analyses. Primary outcome missingness was addressed with last-observation-carriedforward. SAP modifications included Student's t-test use for primary analysis, losartan vs. combined control comparison, and per protocol reporting.

Table 1
Baseline parameters/demographics. Losartan is compared with combined control (lopinavir/ritonavir and placebo) and placebo only control. Statistically significant and 'trend' comparisons are in bold.

Safety
The overall SAE rate was numerically higher with losartan vs. combined control (2.0 vs. 0.6%) and vs. the placebo-only control (2.0 vs. 0%). The overall AE rate trend was similar, being higher with losartan than combined control (3.9 vs. 1.0%) and vs. placebo-only control (3.9 vs. 0%). AKI AE and SAE rates were similar, but hypotension, hyperkalemia, and respiratory failure AE and SAE rates, were numerically higher with losartan than combined and placebo-only controls. No safety comparison was significantly different (Table 3).

Discussion
COVIDMED, the third blinded placebo-controlled RCT assessing an ARB in COVID-19, did not find significant group differences in COSS for hospitalized patients treated with losartan vs. control. An insignificant trend favoring control was found for our primary efficacy outcome, comparison of mean COSS slope of the change vs. placebo-only control (p = 0.05). Our primary safety outcome, overall SAE rate, was numerically but not significantly higher with losartan. Secondary outcomes also numerically favored placebo but no group comparisons were significantly different. We speculate that ARB class adverse effects may overcome theorized benefits making the benefit:risk ratio for these medications in COVID-19 null or negative.
Strengths of our study include: blinded RCT, minimal missingness, and baseline balance. Limitations include small N, early termination, low enrollment (reducing external validity), and SAP alterations.

Conclusion
Although COVIDMED was pilot-like in scope, its results add randomized, blinded, placebo-controlled data to the limited COVID-19 ACEi/ARB literature. Our results are similar to two larger blinded RCTs [17,18]. The totality of the data do not support empiric ACEi/ARB initiation in COVID-19 outside of RCTs.

Table 3
Safety. AE and SAE rates including relatedness. Losartan is compared with combined control (lopinavir/ritonavir and placebo) and placebo only control. Statistically significant and 'trend' comparisons are in bold.
Comparison of SAE rate was the study's primary safety outcome measurement.

Source of funding
This work was supported by a Bassett Research Institute ED Thomas Grant (which included funds to purchase study drugs) and salary support from the Bassett Research Institute and Bassett Medical Center's Department of Internal Medicine. Funders had no role in the design, execution, data analysis, or manuscript preparation or publication of this study.